Kappa‐Selective Opioid Receptor Agonists Leumorphin and Dynorphin Inhibit Supraoptic Neurons in Rat Hypothalamic Slice Preparations

Abstract

Abstract To clarify the effects of opioid peptides, and in particular the effects of kappa-receptor agonists on the activity of supraoptic neurons, extracellular recordings were made from 71 spontaneously firing neurons in the rat hypothalamic slice preparation. Of 71 neurons, 28 showed a phasic firing pattern (phasic neurons: putative vasopressin neurons). The mean firing rate of phasic neurons was 2.6 spikes/s (intraburst firing rate 5.4 +/- 2.2 spikes/s). The mean firing rate of neurons classified as non-phasic neurons (putative oxytocin neurons) was 4.5 spikes/s. Following bath application of leumorphin (LM) at 10(-7) M, which has potent opioid activity at kappa-receptors, 17 (61%) of 28 phasic neurons were inhibited and 22 (51%) of 43 non-phasic neurons were inhibited. Excitation was observed in only one non-phasic neuron. The dose-dependence of the response to LM was tested in five supraoptic neurons. There was an inverse relationship between LM concentration and percent change in firing rate. The threshold concentration of LM was approximately 10(-8) M. The relatively selective kappa-receptor antagonist, MR-2266, completely blocked the LM-induced responses. Its effects were long-lasting and only partial recovery was observed 2 h after the application of MR-2266. Dynorphin had similar inhibitory effects on supraoptic neurons to those obtained with LM when tested on the same neurons. In another series of experiments the mu-receptor agonist morphine and the delta-receptor agonist [D-Ala, D-leu]-enkephalin (DADLE) were applied to 28 supraoptic neurons (12 phasic and 16 non-phasic neurons) at 10(-7) M and their actions compared directly with that of LM. Only two of 12 phasic neurons tested were inhibited by DADLE and none of five phasic neurons tested was inhibited by morphine, while eight of the 12 neurons tested were inhibited by LM. By contrast the non-phasic neurons tested were inhibited by application of each of the peptides; seven of 16 neurons tested were not only inhibited by LM, but also five of 11 neurons by DADLE and seven of 15 by morphine. The magnitude of the responses varied from cell to cell. These results suggest that LM acts at the same receptors as dynorphin, and that opioids acting preferentially at kappa-receptors inhibit both vasopressin and oxytocin neurons while delta- and mu-receptor agonists inhibit primarily oxytocin neurons.